Inhibitors of Phosphodiesterase

PENTOXYPHYLLINE (Trental®) -- This agent, a theobromine derivative, inhibits phosphodiesterase 3 to increase intracellular concentrations of cAMP, acts as an antagonist at adenosine receptors, and may decrease the effects of calcium in cascade events.  It will decrease platelet function and fibrin binding to platelets.  It may also partially inhibit the inflammatory cascade.  It is also reported to increase blood flow by decreasing blood viscosity (thought to be a result of the anti-platelet effects -- although it also reportedly increases the flexibility of red blood cells).  This increase in flexibility (again, thought to be PDE₃ mediated) accounts for its usefulness in intermittent claudication (a symptom of peripheral vascular disease characterised by leg pain upon exertion, due to poor blood flow and subsequent ischaemia).  It may also be used in cardiovascular insufficiency, transient ischaemic attacks, diabetic angiopathy/neuropathy, sickle cell anaemia and thalassaemia (anaemias characterised by red cell deformation and decreased blood flow).  Pentoxyphylline is also being investigated for male infertility due to immotile sperm.  Side effects include GI effects at standard doses and flushing, hypotension, nervousness, agitation, tremors, and seizures possible at higher (toxic) levels.

CILOSTAZOL (Pletal®) -- Cilostazol is a new agent currently used in the treatment of intermittent claudication.  It acts in a manner similar to pentoxyphylline, inhibiting type 3 phosphodiesterase.  The pharmacodynamic effects of cilostazol include inhibition of platelet activity and vasodilatation.  Early clinical trials indicate that cilostazol may be more effective than pentoxyphylline, based upon walking distance without significant pain.  The most common side effects include dizziness, headache, and diarrhoea.  It is metabolised by the cytochrome oxidase system.  Therefore, any drugs that inhibit this pathway (such as diltiazem, erythromycin, ketoconazole, omeprazole, and grapefruit juice) would inhibit the metabolism of cilostazol.

NOTE:  Some clinical data suggests that drugs acting in the manner described above for pentoxyphylline and cilostazol may decrease overall survival  in patients with severe congestive heart failure.

SILDENAFIL (Viagra®) -- Sildenafil is a phosphodiesterase 5 inhibitor used in the treatment of erectile dysfunction.  Mechanistically, at therapeutic doses it selectively inhibits the 5 isozyme of phosphodiesterase.  Recall that PDE₅ is responsible for the metabolism of cGMP, the second messenger for the nitric oxide vasodilating pathway.  This is the primary vasodilatory pathway for the corpus cavernosum, thus increasing inflow of blood and accounting for its efficacy.  At higher levels, this selectively is lost and sildenafil may inhibit PDE₃ and PDE₆  accounting for some of the side effects and toxicity observed with sildenafil.  Other effects attributed to this mechanism include peripheral vasodilatation and inhibition of platelet aggregation.  Sildenafil is metabolised predominantly by the CYP 3A4 pathway with minor metabolism by the CYP 2C9 pathway.  Therefore, some drug interactions may occur.  The primary side effects associated with sildenafil include headache, flushing, and dyspepsia.  Hypotension may occur in some patients and colour blindness occurs in approximately 3%  of patients.  The basis for this colour blindness (which is predominantly seen as loss of blue/green discrimination and is dose-dependent and reversible) is the inhibition of  PDE₆ which is found in the retina and plays a role in phototransduction.

CYCLANDELATE -- This drug, rarely used, is a direct smooth muscle relaxant.  Its proposed mechanism of action is inhibition of phosphodiesterase.  It is used to treat intermittent claudication, thrombophlebitis, arteriosclerosis obliterans (occlusion due to arterial hardening), nocturnal leg cramps, Raynaud's syndrome (a syndrome of young (18-30 y/o) women resulting from abnormal vasoconstriction of the extremities, often resulting from stress or cold, presenting as pallor and cyanosis that may proceed to gangrene -- Raynaud's phenomenon is a similar syndrome that presents secondary to occlusive arterial disease and systemic scleroderma), and cardiovascular insufficiency.  Side effects of cyclandelate include heartburn, GI pain, flushing, headache, weakness, and tachycardia.

PAPAVERINE and ETHAVERINE -- Papaverine and its semisynthetic analogue ethaverine are benzylisoquinoline opioid alkaloids (same class as the anti-tussive noscapine) devoid of activity at endogenous opioid receptors (which are activated by the phenanthrene class of opioid alkaloids such as morphine or codeine).  They directly relax smooth muscle through the inhibition of PDE.  These agents, rarely used now, are primarily prescribed to improve blood flow in cerebral and peripheral ischaemia associated with arterial spasm and myocardial infarction.  Side effects include GI upset, anorexia, vertigo, drowsiness, headache, sweating, and flushing.  Overdose may present as drowsiness, weakness, CNS depression, vision changes, and respiratory depression.

ISOXSUPRINE -- This drug directly relaxes smooth muscle, causing vasodilatation, reportedly through both alpha antagonistic and beta agonistic activity.  It is primarily (though rarely) used to treat cerebrovascular insufficiency.  Side effects include hypotension, tachycardia, chest pain, nausea & vomiting, rash, and weakness.

NYLIDRIN -- This drug also relaxes smooth muscle through beta agonist activity and by another direct mechanism (that is presumably either alpha antagonism or PDE inhibition).  It is used (rarely) to increase blood supply in peripheral vascular disease and cochlear ischaemia.  Side effects of nylidrin include trembling, nervousness, weakness, dizziness, nausea and vomiting, postural hypotension, and palpitations.